Hereditary haemorrhagic telangiectasia
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Regulation of mammalian cellular metabolism by endogenous cyanide production
Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.
Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan
Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants’ understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.
Long-term visit-to-visit blood pressure variability and risk of cardiovascular and bleeding events: insights from the ENGAGE AF-TIMI 48 trial
This post hoc analysis of the ENGAGE AF-TIMI 48 trial assesses differences in cardiovascular and bleeding events according to visit-to-visit blood pressure variability (BPv) in 19,680 patients with a minimum of 4 blood pressure measurements post randomization. Patients were categorized into four groups based on the standard deviation of systolic blood pressure (SBP-SD). In comparisons of the fourth vs first quartile of SBP-SD adjusted for components of the CHA2D2-VASc score and baseline SBP, there were no differences in the odds of stroke, cardiovascular mortality, or all-cause mortality. However, there were statistically significant increases in the risk of major bleeding (OR 1.9, (1.6–2.25)). myocardial infarction (OR 1.42 (1.08–1.87)) and heart failure outcomes (OR 1.49 (1.3–1.72)) in the fourth quartile of BPv. This post-hoc analysis shows that BPv is independently associated with an increased risk of bleeding, MI, and heart failure outcomes in a population with AF on oral anticoagulation.
Commentary: Why is genetic testing underutilized worldwide? The case for hereditary breast cancer
It is thirty years since the BRCA1 and BRCA2 genes were discovered and genetic testing for BRCA1 and BRCA2 was introduced. Despite increasing awareness of the genetic basis of cancer and our evolving knowledge of effective means of prevention, screening, and treatment for hereditary breast and ovarian cancers, genetic testing is underutilized, and most mutation carriers remain unidentified. In this commentary, we explore possible reasons for why this might be so. Our focus is on factors that may influence or deter a patient from pursuing testing, rather than discussing the implications of receiving a positive test result. Issues of concern include an inadequate number of genetic counselors, restrictive (and conflicting) eligibility criteria for testing, the cost of the test, health insurance coverage, fear of future insurance discrimination, privacy issues, lack of familiarity with the testing process in primary care and gaps in both patient and provider knowledge about the impact and the value of testing. We discuss how these factors may lead to the underutilization of genetic testing in North America and throughout the world and discuss alternative models of genetic healthcare delivery. We have invited leaders in cancer genetic from around the world to tell us what they think are the barriers to testing in their host countries.
Breast cancer risk assessment based on susceptibility genes and polygenic risk score in Vietnamese women
Breast screening recommendation based on individual risk assessment is emerging as an alternative approach to improve compliance and efficiency to detect breast cancer (BC) early. In Vietnam, prior knowledge to stratify risk based on genetic factors is currently lacking.
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